We recently identified a novel pathway for the synthesis of brain prostaglandins (PG) from endocannabinoids (eCB). Briefly, the endocannabinoid 2-arachidonoylglycerol (2-AG) is converted to arachidonic acid (AA) by the action of monoacylglycerol lipase (MAGL) providing a phospholipase (PLA2)-independent pool of AA for cyclooxygenase (COX) to initiate synthesis of prostaglandins (PG). The endocannabinoid anandamide (arachidonoyl N-ethanolamide, AEA) can also be converted to AA by FAAH. We previously demonstrated that this pathway can promote neuroinflammation and in preliminary studies we also found that the MAGL antagonist JZ184 dramatically reduced the extent of fever induced by IL-1? or LPS. Thus, in this application we propose experiments to test the hypothesis that this novel pathway regulates temperature homeostasis to central or peripheral inflammatory signals. By using mice deficient in key enzyme of the eCB-PG pathway and pharmacological manipulation of their activity, we will measure the role of MAGL and FAAH in mediating fever response. We will also investigate the effect of pyrogens on the regulation of MAGL and FAAH. We also found that mice null for MAGL, one of the enzymes responsible for the hydrolysis of 2-AG, are resistant to anapyrexia, a life threatening hypothermia often observed during sepsis and severe systemic infection. Thus, we will test the hypothesis that the eCB-PG pathway also plays a role in anapyrexia via synthesis of 2-AG. This will be tested with a combination of pharmacological and transgenic and metabolomics approaches. The eCB-PG pathway is tissue specific and does not occur in the gut, indicating its inhibition may represent a novel antipyretic strategy devoid of the gastrointestinal side effects typically associated with th current use of COX inhibitors. Enzyme regulating the level of 2-AG may represent novel targets for anapyrexia.